This project is part of a Program Project that is a collective research effort todesign highly selective opioid receptor peptide or peptidomimetic ligands for the nonaddictive treatment of pain and drug dependency. The objective of this project is to elucidate which molecular characteristics of opioid receptor ligands may be modified to increase their passive transport from the blood to receptor sites in the brain. This necessarily involves permeation through biological membranes that compose the blood-brain barrier. In order to understand the passive permeation of these ligands through membrans we have adopted a biophysical approach to analyze the permeation in terms of the water-to-membrane partition, transmembrane diffusion, and membrane-water interfacial interactions. These studies include both (1) the determination of the rate of peptide permeation as a fuction of the peptide structure and the membrane composition; and (2) the characterization of the thermodynamics of ligand transfer from water to the membrane. The later includes the determination of partition coefficients via an equililbrium dialysis procedure developed (in this project) for these peptides, and isothermal titration calorimetry to directly measure the enthalpy of peptide-membrane binding. Taken together these data provide the necessary information to ascertain which elements of the peptide ligand may be usefully modified to enhance its membrane permeation. The above results will be correlated with molecular structural information (from NMR and computatinal studies in other projects of this Program Project) to design new opioid ligands that amplify the effective modes of transfer across membranes. The two major classes of opioid teceptor peptides that have been studied to data are the highly selrctive delta receptor ligand, DPDPE and its analogs, and the potenti analgesic, biphalin and its analogs. Future studies will include new modifications of these two peptides, as well as prodrugs of this peptides, new cyclic and acyclic deltorphins, and other peptides and peptidomimetics proposed in Project 0001 that prove to be especially bioactive.